The aim of this project is to understand the neurotoxic effect of lead, a heavy metal that binds with high affinity t glutathione and metallothionein. Both polypeptides play as important role in Cu/Zn homeostasis as well as removal of free oxygen radicals and the breakdown of their function may be linked to the etiology of various progressive neurological diseases. Exposure of mesencephalic primary cultures to 25 uM Pb2+ for 24 h to 72 h increased that metallothioneinI/II immunoreactive protein band by 2- to 9-fold, respectively. A similar treatment increased the glutathione content of these cells by 2-fold. In contrast, glutamine synthetase, another glia-specific enzyme, was not altered by 25 uM Pb2+ but was decreased by 100 or 200 uM Pb2+. Studies on cytoskeletal proteins showed that the immunoreacrice protein bands of MAP-2, tauprotein and glial fibrillary protein were decreased after a 24 h exposure to 25 uM Pb2+. Our results indicate that Pb2+ induces metallothioneinI/II but may also displace Zn2+ from its metallothionein binding sites and thereby interfere with gene transcription.